(1-azabicyclo[2.2.2]oct-3-yl) (1,2,3,4-tetrahydronaphthalen-1-ylmethyl)amine and n-(1-azabicyclo[2.2.2]oc

ABSTRACT

Compounds of Formula 6: ##STR1## in which R 1  and R 2  are each hydrogen or together form ═O.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 08/280,265, filedJul. 26, 1994 now U.S. Pat. No. 5,510,486.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a novel process for preparing2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneand the pharmaceutically acceptable salts thereof, which are 5-HT₃receptor antagonists. This invention also relates to compounds which areintermediates useful for preparing2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneand pharmaceutically acceptable salts thereof.

2. Description of the Field

2-(1-Azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneand2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-oneand the pharmaceutically acceptable salts, individual stereoisomers andmixture of stereoisomers thereof are 5-HT₃ receptor antagonists. Inaddition,2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-oneand the salts, individual stereoisomers and mixture of stereoisomersthereof are useful in the preparation of2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one.Methods for using these 5-HT₃ antagonists and certain processes fortheir preparation, different from those described herein, are describedin U.S. Pat. No. 5,202,333.

SUMMARY OF THE INVENTION

This invention relates to a process for preparing2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneand pharmaceutically acceptable salts, individual stereoisomers andmixtures of stereoisomers thereof, which process comprises:

(A) reacting a compound of Formula 5: ##STR2## in which L is a leavinggroup, with 1-azabicyclo[2.2.2]oct-3-ylamine to giveN-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide;

(B) reducing theN-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamideto give(1-azabicyclo[2.2.2]oct-3-yl)-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)amine;

(C) reacting the(1-azabicyclo[2.2.2]oct-3-yl)(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)aminewith a formylating agent and then treating with a Lewis acid to give2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one;

(D) optionally separating a diastereomeric mixture of2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneinto individual stereoisomers or mixtures of stereoisomers;

(E) optionally converting2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneto a pharmaceutically acceptable acid addition salt; and

(F) optionally converting an acid addition salt of2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneto non-salt form.

A second aspect of the invention relates to a compound of Formula 6:##STR3## in which R¹ and R² are each hydrogen or together form ═O; andthe salts, individual stereoisomers and mixture of stereoisomersthereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein:

"Leaving group" has the meaning conventionally associated with it insynthetic organic chemistry, i.e., an atom or group displaceable underalkylating conditions, and includes halo, (C₁₋₄)alkyloxy (e.g., methoxy,ethoxy and the like), aryloxy (e.g., phenyloxy and the like),(C₁₋₄)alkylthio (e.g., methylthio, ethylthio and the like), arylthio(e.g., phenylthio and the like) and alkane- or arenesulfonyloxy (e.g.,mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy,trifluoromethanesufonyloxy, tosyloxy and the like).

"Pharmaceutically acceptable" means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

"Acid addition salts" means salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2,-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid p-chlorobenzenesulfonic acid, 2-naphthalenesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like.

"Pharmaceutically acceptable acid addition salts" are salts which arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity.

"Optional" or "optionally" means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, "optionally converting the2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneto a pharmaceutically acceptable acid addition salt" means that theconversion to the acid addition salt may or may not be carried out inorder for the process described to fall within the invention, and theinvention includes those processes wherein the conversion occurs andthose processes in which it does not.

Isomerism is the phenomenon wherein compounds have identical molecularformulae but differ in the nature or sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed "stereoisomers".Stereoisomers that are not mirror images of one another are termed"diastereomers" and stereoisomers that are nonsuperimposable mirrorimages are termed "enantiomers" or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a "chiralcenter".

A compound with one chiral center has two enantiomeric forms of oppositechirality and may exist as either an individual enantiomer or as amixture of enantiomers. A mixture containing equal amounts of individualenantiomeric forms of opposite chirality is termed a "racemic mixture".A compound that has more than one chiral center has 2^(n-1) enantiomericpairs, where n is the number of chiral centers. Compounds with more thanone chiral center may exist as either an individual diastereomer or as amixture of diastereomers, termed a "diastereomeric mixture". For thepurposes of this application, a mixture of stereoisomers containing oneor more enantiomeric pairs is termed an "enantiomeric mixture" and amixture of stereoisomers without their respective enantiomers present istermed a "non-enantiomeric mixture".

When one chiral center is present a stereoisomer may be characterized bythe absolute configuration of that chiral center. Absolute configurationrefers to the arrangement in space of the substituents attached to thechiral center. The substituents attached to the chiral center underconsideration are ranked in accordance with the Sequence Rule of Cahn,Ingold and Prelog and the absolute descriptor R or S is cited inparentheses followed by a hyphen and the chemical name of compound(e.g., (S)-1-azabicyclo[2.2.2]oct-3-ylamine).

For the purposes of this application, when two or more chiral centersare present, the descriptor is cited immediately following the number ofthe chiral center as it appears in the name of the compound (e.g,1-azabicyclo[2.2.2]oct-3S-yl). When a chiral center can be of eitherconfiguration individually or as a mixture thereof, in equal amounts orotherwise, no descriptor will appear. Accordingly, the compound ofFormula 1 in which each of the chiral centers are in an S-configuration,that is, the compound of the following formula: ##STR4## is referred toas2-(1-azabicyclo[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one.

Preferred Embodiments

While the broadest definition of this invention is set forth in theSummary of the Invention, compounds of Formula 6 and certain processesfor the preparation of compounds of Formula i are preferred. Forexample, a preferred compound of Formula 6 is the S,S-stereoisomerthereof, namelyN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamideor(1-azabicyclo[2.2.2]oct-3S-yl)(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine.

A preferred process for preparing2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneis that in which L is chloro and the 1-azabicyclo[2.2.2]oct-3-ylamine is(S)-1-azabicyclo[2.2.2]oct-3-ylamine and is reacted with the compound ofFormula 5 to giveN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide;and preferably wherein theN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamideis then reduced asN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide.

Processes of the Invention

The process of this invention is depicted in the following reactionscheme: ##STR5## in which L is a leaving group, Formulae 1, 2 and 3represent an individual diastereomer or a diastereomeric mixture,enantiomeric or otherwise, and Formulae 4 and 5 represent an individualenantiomer or an enantiomeric mixture, racemic or otherwise.

2-(1-Azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one(Formula 1) is prepared by reacting(1-azabicyclo[2.2.2]oct-3-yl)(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)amine(Formula 2) with a suitable formulating agent (e.g., trichloromethylchloroformate, 4-chlorophenyl chloroformate, 4-nitrophenylchloroformate, triphosgene, phosgene, etc., preferably trichloromethylchloroformate) and then treating with a suitable Lewis acid (e.g., borontrifluoride etherate, aluminum chloride, etc., preferably borontrifluoride etherate). The reaction with the chloroformate is carriedout under a nitrogen atmosphere and in a suitable solvent, typically anaromatic hydrocarbon or ether and preferably an aromatic hydrocarbon(e.g., toluene, chlorobenzene, tetrahydrofuran (THF), etc., preferablytoluene), at 50° to 132° C., typically at 95° to 125° C. and preferablyat approximately 110° C., and requires 1 to 12 hours.

The treatment with the Lewis acid is carried out in a suitable solvent,typically an aromatic hydrocarbon (e.g., toluene, chlorobenzene, etc.)and preferably toluene, at 110° to 132° C., typically at 110° to 120° C.and preferably at approximately 110° C., and requires 4 to 18 hours. Thepreparation of a compound of Formula 1 is described in Example 6.

The compound of Formula 2 is prepared by reducingN-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide(Formula 3). Reduction of the carboxamide is carried out with a chemicalreducing agent, preferably borane, and in a suitable solvent, typicallyan ether and preferably THF, at reflux temperature, and requires 1 to 3hours. The preparation of a compound of Formula 2 is described inExample 5.

The compound of Formula 3 is prepared by reacting a compound of Formula5 with 1-azabicyclo[2.2.2]oct-3-ylamine (Formula 4). The reaction iscarried out in a suitable solvent, typically a mixture of ester andaromatic hydrocarbon and preferably 4/1 to 3/1 ethyl acetate/toluene, at25° to 50° C., typically at 40° to 50° C. and preferably atapproximately 50° C., and requires 2 to 6 hours. The preparation of acompound of Formula 3 is described in Example 3.

1-Azabicyclo[2.2.2]oct-3-ylamine is commercially available or can bereadily prepared by methods know to those of ordinary skill in the art.The compound of Formula 5 can be prepared by carboxylating1,2,3,4-tetrahydronaphthalene to give 1,2,3,4-tetrahydro-1-naphthoicacid and then creating leaving group L. The carboxylation is carried outby treating the 1,2,3,4-tetrahydronaphthalene with strong base,preferably n-butyl potassium, and then reacting with carbon dioxide. Thetreatment with base and subsequent reaction with carbon dioxide iscarried out in a suitable solvent, preferably hexane, at -78° to 20° C.,typically at -50° to 20° C. and preferably at approximately 20° C., andrequires 18 to 24 hours. The preparation of1,2,3,4-tetrahydro-1-naphthoic acid is described in Example 1.

Creation of the leaving group L can be effected by treating thenaphthoic acid with an agent such as methanesulfonyl chloride,thionylchloride, phosphorous pentachloride, phosphorous oxychloride, andthe like. For example, a compound of Formula 5 in which L is chloro(i.e., 1,2,3,4-tetrahydro-1-naphthoic acid chloride) can be prepared byreacting 1,2,3,4-tetrahydro-1-naphthoic acid with thionylchloride in asuitable solvent, typically an aromatic hydrocarbon or halogenatedhydrocarbon (e.g., toluene, methylene chloride, etc. preferablytoluene), at 25° to 50° C., typically at 40° to 50° C. and preferably atapproximately 50° C., and requires 1 to 2 hours.

Depending upon the reaction conditions, isolation/separation techniquesand starting materials, the compounds of Formulae 1, 2, 3, 4 and 5 maybe converted to or prepared as their non-salt or salt forms. Thecompounds of Formulae 1, 2, 3, 4 and 5 in the processes of thisinvention as its non-salt or acid addition salt form in order for theprocess described to fall within the invention, and the inventionincludes those processes wherein the compounds of Formulae 1, 2, 3, 4and 5 are in non-salt form and those processes wherein the compounds areacid addition salts. Accordingly, while some forms of the compounds ofFormulae 1, 2, 3, 4 and 5 are preferred, unless indicated otherwise, thedescription or naming of a particular compound in the specification orin the claims is intended to include both the non-salt form and saltforms, pharmaceutically acceptable or otherwise, thereof.

The compounds of Formulae 1, 2, 3, 4 and 5 each contain one or morechiral centers and can be separated into or prepared as individualstereoisomers and/or mixtures of stereoisomers. Accordingly, while somestereoisomers or mixtures of stereoisomers of the compounds of Formulae1, 2, 3, 4 and 5 are preferred, unless indicated otherwise, thedescription or naming of a particular chiral compound in thespecification or in the claims is intended to include individualstereoisomers and the mixtures, racemic or otherwise, thereof.

The individual stereoisomers of the compound of Formula 1 can beseparated from a non-enantiomeric diastereomeric mixture of the compoundof Formula 1 by chromatography, by separation/resolution techniquesbased upon differences in solubility, by direct or selectivecrystallization or by any other method known to one of ordinary skill inthe art. For example,2-(1-azabicyclo[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-onehydrochloride is readily prepared from a diastereomeric mixture of2-(1-azabicyclo[2.2.2]oct-3S-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-onehydrochloride by repeated crystallization from a suitable solvent,typically an alcohol and preferably isopropanol.

A non-enantiomeric diastereomeric mixture of the compound of Formula 1can be prepared by reacting an enantiomeric diastereomeric mixture withan optically active acid (e.g., tartaric acid, mandelic acid, malicacid, the 2-arylpropionic acids in general, camphorsulfonic acid, etc.)to form diastereomeric crystalline salts. The non-enantiomericdiastereomeric mixture of crystalline salts are then separated intoindividual diastereomers by any of the methods described above and thepure diastereomers of the compound of Formula 1 are recovered, alongwith the optically active acid, by any practical means that would notresult in racemization. A more detailed description of the techniquesapplicable to the preparation of stereoisomers can be found in JeanJacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates andResolutions, John Wiley & Sons, Inc. (1981).

Alternatively, a non-enantiomeric diastereomeric mixture of the compoundof Formula 1 can be prepared by proceeding as described above andreacting a non-enantiomeric diastereomeric mixture of a compound ofFormula 2 with the formulating agent and then treating with a Lewisacid. A non-enantiomeric diastereomeric mixture of a compound of Formula2 can be prepared by proceeding as described above and reducing anon-enantiomeric diastereomeric mixture of the compound of Formula 3. Anon-enantiomeric diastereomeric mixture of the compound of Formula 3 canbe prepared by proceeding as described above and reacting an individualenantiomer of the compound of Formula 4 with an enantiomeric mixture ofthe compound of Formula 5 or by reacting an individual enantiomer of thecompound of Formula 5 with an enantiomeric mixture of the compound ofFormula 4.

Similarly, the individual diastereomers of the compound of Formula 1 canbe prepared by proceeding as described above and reacting an individualdiastereomer of the compound of Formula 2 with the formylating agent andthen treating with a Lewis acid. The individual diastereomers of thecompound of Formula 2 can be prepared from a diastereomeric mixture of acompound of Formula 2 by any of the separation/resolution techniquesdescribed above or by proceeding as described above and reducing anindividual diastereomer of the compound of Formula 3.

The individual diastereomers of the compound of Formula 3 can beprepared from a diastereomeric mixture of a compound of Formula 3 by anyof the separation/resolution techniques described above. For example,N-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamideis readily prepared fromN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamideby repeated crystallization from a suitable solvent, typically aaromatic hydrocarbon and preferably toluene. The preparation ofN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamideis described in Example 4.

Alternatively, the individual diastereomers of the compound of Formula 3can be prepared by proceeding as described above and reacting anindividual enantiomer of the amine of Formula 4 with an individualenantiomer of the compound of Formula 5. The individual enantiomers ofthe compound of Formula 5 can be prepared from the correspondingenantiomer of 1,2,3,4-tetrahydro-1-naphthoic acid. The individualenantiomer of the naphthoic acid is conveniently prepared by reacting aenantiomeric mixture with a suitable optically active base. For example,the (S)-1,2,3,4-tetrahydro-1-naphthoic acid can be prepared by reactingan enantiomeric mixture of the acid with quinine in a suitable solvent(e.g., ethanol, acetone, etc. preferably ethanol), selectivelycrystallizing the quinine salt and then isolating the optically activeacid. The preparation of (S)-1,2,3,4-tetrahydro-1-naphthoic acid isdescribed in Example 2.

The individual enantiomers of the amine of Formula 4 can be separatedfrom a enantiomeric mixture of the amine of Formula 4 by any of theapplicable separation/resolution techniques described above.Alternatively, (S)-1-azabicyclo[2.2.2]oct-3-ylamine can be prepared byreacting 1-azabicyclo[2.2.2]oct-3-one with an (R)-α-alkylbenzylamine,preferably (R)-1-phenylethylamine, to give the corresponding(R)-N-(α-alkylbenzyl)-3-(1-azabicyclo[2.2.2]octan)imine, reducing theimine to give the correspondingN-(1R-phenylalkyl)-1-azabicyclo[2.2.2]oct-3S-ylamine and thenhydrogenolyzing. The reaction with the (R)-α-alkylbenzylamine is carriedout in the presence of lithium oxide in a suitable organic solvent,typically an ether and preferably THF, at 10° to 40° C., typically at15° to 30° C. and preferably at approximately 20° C., and requires 12 to84 hours. The reduction of the imine can be carried out by catalytichydrogenation or with a suitable chemical reducing agent.

Hydrogenation of the imine is carried out in the presence of a suitablecatalyst, preferably 5% Pt/C, and in a suitable organic solvent,typically an alcohol and preferably ethanol, at 10° to 40° C., typicallyat 15° to 30° C. and preferably at approximately 20° C., and at 0 to 100psig, typically at 5 to 50 psig and preferably at approximately 20 psig,and requires 1 to 48 hours. Alternatively, the imine can be reduced witha suitable chemical reducing agent, preferably an alkali borohydride(e.g., sodium borohydride, lithium borohydride, etc., preferably sodiumborohydride), in a suitable organic solvent, typically an alcohol andpreferably ethanol, at -15° to 50° C., typically at 15° to 30° C. andpreferably at approximately 20° C., and requires 15 minutes to 3 hours.

The hydrogenolyzation is effected by hydrogenation theN-(1R-phenylalkyl)-1-azabicyclo[2.2.2]oct-3S-ylamine in the presence ofa suitable catalyst (e.g., 10% Pd/C, 20% Pd/C, etc., preferably 10%Pd/C) and in a suitable organic solvent, typically an alcohol and watermixture and preferably 5/1 to 2/1 ethanol/water, at 10° to 40° C.,typically at 15° to 30° C. and preferably at approximately 20° C., andat 0 to 100 psig, typically at 0 to 20 psig and preferably atapproximately 5 psig, and requires 5 to 48 hours. Proceeding similarlybut replacing the (R)-α-alkylbenzylamine with (S)-α-alkylbenzylamine,(R)-1-azabicyclo[2.2.2]oct-3-ylamine can be prepared.

Thus, the compounds of Formulae 1, 2, 3, 4 and 5 may exist as individualstereoisomers and/or any mixture of stereoisomers in order for theprocess described to fall within the invention, and the inventionincludes those processes wherein individual stereoisomers are used andthose processes wherein mixtures of stereoisomers are used. An exemplarymethod of practicing the processes of this invention comprises:

(A) reacting 1,2,3,4-tetrahydro-1-naphthoic acid chloride with(S)-1-azabicyclo[2.2.2]oct-3-ylamine to give a diastereomeric mixtureN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide;

(B) separating the diastereomeric mixture ofN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamideinto individual diastereomers and reducingN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamideto give(1-azabicyclo[2.2.2]oct-3S-yl)-(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine;

(C) reacting the(1-azabicyclo[2.2.2]oct-3S-yl)(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)aminewith a formylating agent and then treating with a Lewis acid to give2-(1-azabicyclo[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one;and

(D) converting the2-(1-azabicyclo[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-oneto a pharmaceutically acceptable acid addition salt.

While the process steps described immediately above represent oneparticular method of practicing the processes of the invention, itshould be understood that other variations in the process steps canoccur without deviating from the scope of the invention. For example,(S)-1,2,3,4-tetrahydro-1-naphthoic acid chloride can be reacted with(S)-1-azabicyclo[2.2.2]oct-3-ylamine to giveN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamidewhich is reduced to give(1-azabicyclo[2.2.2]oct-3S-yl)(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine.

EXAMPLE 1 1,2,3,4-Tetrahydro-1-naphthoic Acid

A mixture of potassium tert-butoxide (74.13 g, 661 mmol) andN,N,N',N'-tetramethylethylenediamine (6.63M, 78.92 mL, 523 mmol) in 1.7L of hexane was cooled to below -30° C. under a nitrogen atmosphere andthen n-butyl lithium (1.6M, 327 mL, 523 mmol) was added over 15 minutes.The mixture was stirred for 15 minutes and 1,2,3,4-tetrahydronapthalene(7.36M, 85.27 mL, 623 mmol) was added. The mixture was stirred for 6hours at 0° C. and then for 18 hours at between 0° and 20° C. Themixture was aerated with carbon dioxide for approximately 30 minutes andthen approximately 1.2 L of water was added. The aqueous layer wasseparated, cooled in an ice-water bath and acidified with approximately185 mL of 12N hydrochloric acid. The mixture was then extracted withethyl acetate (2×1 L) and the combined ethyl acetate layers were dried(NaSO₄). The mixture was filtered and concentrated. The residue wasdissolved in 170 mL of formic acid and then the solution was dilutedwith 340 mL of water to give a crystalline product. The product wasisolated by filtration, washed with 40 mL of water and dried. The drymaterial was dissolved in 0.74 L of ethyl acetate and the solution waswashed with 0.5 L of water, dried (Na₂ SO₄) and concentrated to give1,2,3,4-tetrahydro-1-naphthoic acid (38.68 g, 219.6 mol), m.p.74.4°-79.2° C.

EXAMPLE 2 (S)-1,2,3,4-Tetrahydro-1-naphthoic Acid

A solution of 1,2,3,4-tetrahydro-1-naphthoic acid (50.66 g, 290 mmol)and quinine (93.67 g, 290 mmol) in 937 mL of ethanol and 150 mL of waterwas cooled to approximately 0° C., seeded with crystals of(S)-1,2,3,4-tetrahydro-1-naphthoic acid and allowed to stand forapproximately 24 hours to give a precipitate. The precipitate wasisolated by filtration and dried. The dry crystals were crystallizedfrom 540 mL of ethanol, filtered and dried to give quinine salt (46.18g, 92 mmol).

The quinine salt was suspended in 180 mL of ethyl acetate and thesuspension was washed with 1N hydrochloric acid (2×92 mL). The mixturewas then dried (NaSO₄), filtered and concentrated. The residue wasdissolved in hexane and crystallized to give(S)-1,2,3,4-tetrahydro-1-naphthoic acid (14.27 g 0.08 mol), m.p. 54°-56°C. [α]_(D) -62.76° (c=1.0165, benzene).

EXAMPLE 3N-(1-Azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide

A mixture of 1,2,3,4-tetrahydro-1-naphthoic acid (207.75 g, 1.18 mol),prepared as in Example 1, and thionyl chloride (13.7M, 92.89 mL, 1.27mol) in 20 drops of N,N-dimethylformamide and 795 mL of toluene wasstirred for 1 hour at 25° C. and for 1 hour at 50° C. The mixture wasdistilled to a volume of approximately 500 mL and then diluted with 300mL of toluene.

(S)-1-Azabicyclo[2.2.2]oct-3-ylamine (148.83 g, 1.16 mol) in 2.895 L ofethyl acetate was added and the mixture was stirred for 1 hour at 50° C.The mixture was allowed to cool to room temperature and 2 L of water and93.4 mL of 50% sodium hydroxide were added. The aqueous layer wasseparated and extracted with ethyl acetate (2×1.5 L). The combined ethylacetate layers were dried (NaSO₄), filtered and concentrated to giveN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide(350.3 g, 1.23 mol), m.p. 190.1°-191.2° C.

Proceeding as in Example 3, but replacing 1,2,3,4-tetrahydro-1-naphthoicacid with (S)-1,2,3,4-tetrahydro-1-naphthoic acid, prepared as inExample 2, gaveN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide,m.p. 190°-191° C. [α]_(D) -51.26° (c=1.0145, methylene chloride).

EXAMPLE 4N-(1-Azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide

N-(1-Azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide(350.3 g, 1.23 mol), prepared as in Example 3, was dissolved in 1.4 L ofboiling toluene and the solution was cooled to give a crystallineprecipitate. The precipitate was isolated by filtration and dried togive a diastereomeric mixture of 82%N-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide(A) and 18%N-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1R-ylcarboxamide(B) (128.63 g, 0.45 mol).

The 82% A/18% B mixture was dissolved in 514 mL of boiling toluene andthe solution was cooled to give a crystalline precipitate. Theprecipitate was isolated by filtration and dried to give 92.5% pureN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide(110.17 g, 0.39 mol), m.p. 190°-191° C. [α]_(D) -26.24° (c=2.004,methylene chloride).

EXAMPLE 5(1-Azabicyclo[2.2.2]oct-3S-yl)(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine

A mixture ofN-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide(85 g, 0.3 mol), prepared as in Example 3 or 4, and sodium borohydride(45.22 g) in 1.7 L of THF was cooled to below 15° C. Boron trifluorideetherate (8.1M, 195.92 mL, 1.59 mol) was added over 20 minutes and themixture was stirred for 30 minutes at room temperature and then atreflux for 2 hours. The mixture was cooled to below 20° C. and 1.222 Lof 2N hydrochloric acid was added slowly. The mixture was distilled to avolume of approximately 1.4 L. The remaining mixture was cooled and 50%potassium hydroxide (512 g) was added. The mixture was extracted withethyl acetate (1×1.2 L and 2×500 mL). The combined ethyl acetate layerswere dried (NaSO₄), filtered and concentrated to give(1-azabicyclo[2.2.2]oct-3S-yl)-(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine(80.96 g, 0.3 mol) as an oil. [α]_(D) -32.01° (c=1.0185, methylenechloride).

EXAMPLE 6 2-(1-Azabicyclo[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one hydrochloride

A solution of(1-azabicyclo[2.2.2]oct-3S-yl)(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine(80.15 g, 0.3 mol), prepared as in Example 5, in 0.81 L of toluene washeated to reflux under a nitrogen atmosphere and then cooled to 25° C.Trichloromethyl chloroformate (8.3M, 25.28 mL, 0.21 mmol) in 100 mL oftoluene was added at a rate such that the temperature of the mixtureremained below 50° C. The mixture was stirred for approximately 18 hoursand then boron trifluoride etherate (8.1M, 110.28 mL, 0.893 mol wasadded. The mixture was heated at reflux for 5 hours, cooled to 30° C.and then 455 mL of 2N hydrochloric acid and 455 mL of water were added.The mixture was heated at reflux for 1 hour, cooled to 10° C. and then50% potassium hydroxide (200 g) was added at a rate such that thetemperature of the mixture remained below 40° C. The mixture was addedto 0.8 L of ethyl acetate and filtered. The aqueous layer was separatedand extracted with ethyl acetate (2×0.6 L). The combined ethyl acetatelayers were concentrated and the residue was dissolved in 1.08 L ofisopropanol. The solution was treated with 82 mL of 4N hydrogen chloridein ethanol and cooled to below 5° C. to give a crystalline precipitate.The precipitate was isolated by filtration and dried to give 75.06 g ofsolid material.

The solid material was dissolved in 1.2 L of isopropanol and 60 mL ofwater at reflux temperature and then 500 mL of additional isopropanolwas added. The mixture was distilled to a volume of approximately 1.2 Land then allowed to cool to room temperature. The mixture was cooled inan ice-water bath for 2 hours to give a crystalline product. The productwas isolated by filtration to give2-(1-azabicyclo[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-onehydrochloride (64.41 g, 0.19 mol), m.p. 303° C. (dec). [α]_(D) 90.4°(c=1, chloroform).

We claim:
 1. A compound of Formula 6: ##STR6## in which R¹ and R² are each hydrogen or together form ═O.
 2. The compound of claim 1 in which R¹ and R² are each hydrogen, namely (1-azabicyclo[2.2.2]oct-3-yl)(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)amine.
 3. The compound of claim 2 which is (1-azabicyclo[2.2.2]oct-3S-yl)-(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine.
 4. The compound of claim 1 in which R¹ and R² together form ═O, namely N-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide.
 5. The compound of claim 4 which is N-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide. 